Nrf2 protects stellate cells from Smad-dependent cell activation

PloS One
Vincenzo Prestigiacomo, Laura Suter-Dick

Abstract

Hepatic stellate cells (HSC) orchestrate the deposition of extracellular matrix (ECM) and are the primary effector of liver fibrosis. Several factors, including TGF-β1, PDGF and oxidative stress, have been shown to trigger HSC activation. However, the involvement of cellular defence mechanisms, such as the activation of antioxidant response by Nrf2/Keap1 in the modulation of HSC activation is not known. The aim of this work was to elucidate the role of Nrf2 pathway in HSC trans-differentiation involved in the development of fibrosis. To this end, we repressed Nrf2 and Keap1 expression in HSC with specific siRNAs. We then assessed activation markers, as well as proliferation and migration, in both primary and immortalised human HSCs exposed to Smad inhibitors (SB-431542 hydrate and SB-525334), TGF-β1 and/or PDGF. Our results indicate that knocking down Nrf2 induces HSC activation, as shown by an increase in αSMA-positive cells and by gene expression induction of ECM components (collagens and fibronectin). HSC with reduced Nrf2-levels also showed an increase in migration and a decrease in proliferation. We could also demonstrate that the activation of Nrf2-deficient HSC involves the TGF-β1/Smad pathway, as the activation was succ...Continue Reading

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Citations

May 28, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Matthew McMillinSharon DeMorrow
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Methods Mentioned

BETA
nuclear translocation
Transfection
PCR
fluorescence microscopy
ELISA
confocal microscopy

Software Mentioned

Corbett Rotorgene Analysis Software
Heatmapper
ImageJ Healing
ImageJ
Image J
GraphPad Prism

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